2-methylindole-4-acetic acid, process for producing the same, and process for producing intermediate therefor

ABSTRACT

2-Methylindole-4-acetic acid, which is represented by the formula (I) and is an intermediate for an important indole derivative as medicines; and a process for producing the compound and the synthetic intermediates.  
     The process for producing 2-methylindole-4-acetic acid and synthetic intermediates is described in this invention. As shown in formula (I), 2-methylindole-4-acetic acid is an intermediate of important indole derivative which is useful tools for medicine.  
                 
 
     According to the process described in this invention, 2-methylindole-4-acetic acid, which is an intermediate of important indole derivative as medicines, can be produced in high yield using inexpensive reagents under mild conditions which are suitable for industrial production.

TECHNICAL FIELD

[0001] The invention relates to 2-methylindole-4-acetic acid, processfor producing the same, and process for producing intermediate therefor.

[0002] More specifically, the invention relates to2-methylindole-4-acetic acid represented by formula (I), which is anintermediate of medicine:

[0003] process for producing the same, and process for producingintermediate therefor.

BACKGROUND ART

[0004] As shown in formula (I), 2-methylindole-4-acetic acid is anintermediate of indole derivatives, which is important for medicine, andit is a novel compound.

[0005] As a compound similar to the compound represented by the formula(I), for example, the following are known.

[0006] (1) A preparation of indole-4-acetic acid that is represented bya scheme:

[0007] (wherein Ts represents tosyl group) has been published in J. Org.Chem., 44(22), 4003-4005 (1979).

[0008] (2) Also, the preparation of 1-tosylindole-4-acetic acid or4-cyanomethyl-1-tosylindole that is represented by a scheme:

[0009] (wherein X represents CN or COOC₂H₅) has been published inHererocycles, 24(9), 2611-2618 (1986).

[0010] As a process for the preparation of2-methyl-4-oxo-4,5,6,7-tetrahydroindole that is a intermediate of thecompound represented by the formula (I) of the present invention,

[0011] (3) a process for the preparation represented by a scheme:

[0012] has been published in the specification of U.S. Pat. No.4,868,315,

[0013] (4) a process for the preparation represented by a scheme:

[0014] has been published in Justus Liebigs Ann. Chem., 655, 20-26(1962), and

[0015] (5) a process for the preparation represented by a scheme:

[0016] has been published in the specification of JP2-15058.

[0017] Also, as a compound similar to2-methyl-4-oxo-4,5,6,7-tetrahydroindole,

[0018] (6) a process for the preparation represented by a scheme:

[0019] (wherein R represents H or CH₃, R′ represents H, CH₃ or—CH₂—C₆H₅) has been published in J. Org. Chem., 43(18), 3541-3544(1978).

[0020] As a similar process of halogenation reaction that is one of theprocess of the compound represented by the formula (I) of the presentinvention,

[0021] (7) A process for the preparation of a halogen compoundrepresented by a scheme:

[0022] has been published in Hererocycles, 23(1), 165-170 (1985).

DISCLOSURE OF THE INVENTION

[0023] The process for the preparation of 2-methylindole-4-acetic acid,which is an intermediate in medicine, under mild condition, usinginexpensive reagents, and in high yield is desired. Especially, theprocess for the preparation of the compound industrially is desired.

[0024] The present inventors have energetically studied to find theprocess for the preparation of the 2-methylindole-4-acetic acid in highyield using inexpensive reagents under mild conditions suitable forindustrial production. As a result, the novel process for thepreparation represented by following scheme 1 was found out and thepresent invention was completed. 2-Methylindole-4-acetic acidrepresented by the formula (I) is a novel compound.

[0025] In the reaction scheme 1, R¹ represents C₁₋₄ alkyl and Tsrepresents tosyl group.

[0026] For example, the compound represented by the formula (II-a),(II-b) and (IV) may be prepared according to the following reactionschemes 2 and 3.

[0027] In the reaction scheme 2 and 3, X represents halogen atom, R¹represents C₁₋₄ alkyl, R² represents trifluoromethyl, phenyl or phenylsubstituted by methyl, chloro or nitro at p-position.

[0028] Also, for example, the compound represented by the formula (X),which is the starting material in reaction scheme 2, can be preparedaccording to reaction scheme 4. In the scheme, X represents halogenatom.

[0029] In the present invention, halogen atom is, chloride, bromide,iodide and fluoride.

[0030] In the present invention, C₁₋₄ alkyl is methyl, ethyl, propyl,butyl and isomers thereof.

[0031] In the reaction scheme 1, the reaction of step [a]is a hydrolysisreaction under alkali condition, for example, it is carried out in awater-miscible organic solvent (e.g. ethanol, methanol, isopropanol,ethyleneglycol dimethyl ether, tetrahydrofuran (THF) or a mixturethereof), using an aqueous solution of an alkali (e.g. sodium hydroxide,potassium hydroxide) at reflux temperature of the solvent.

[0032] The reaction of step [b] is a decarboxylation reaction, forexample, it is carried out in a solvent (e.g. acetic acid, water or amixture thereof), using an acid (e.g. acetic acid, sulfuric acid,hydrochloric acid) at 25˜150° C.

[0033] The reaction of step [c] is a hydrolysis reaction under alkalicondition, for example, it is carried out in a water-miscible organicsolvent (e.g. ethanol, methanol, isopropanol, ethyleneglycol dimethylether, tetrahydrofuran (THF) or a mixture thereof), using an aqueoussolution of an alkali (e.g. sodium hydroxide, potassium hydroxide) atreflux temperature of the solvent.

[0034] In the reaction scheme 2, the reaction of step [d] is atosylation reaction, for example, it is carried out in an organicsolvent (e.g. acetonitrile, THF, ethyleneglycol dimethyl ether,diglyme), in the presence of a quaternary ammonium salt (e.g.tetrabutylammonium bromide) and an aqueous solution of an alkali (e.g.sodium hydroxide, potassium hydroxide) using tosyl halide (e.g. tosylchloride, tosyl fluoride) at 0˜50° C.

[0035] The reaction of step [e-1] is a carbon elongation reaction, forexample, [e-1-a] it is carried out using Dean Stark equipment, in anorganic solvent (e.g. toluene, xylene), in the presence of ammoniumacetate and an organic acid (e.g. acetic acid, propionic acid), usingcyanoacetic acid ester (e.g. methyl cyanoacetate, ethyl cyanoacetate) atreflux temperature of the solvent, or [e-1-b] it is carried out usingDean Stark equipment, in an organic solvent (e.g. toluene, xylene,benzene), in the presence of primary amine (e.g. cyclohexylamine,n-octyl amine) and an organic acid (e.g. acetic acid, propionic acid),using cyanoacetic acid ester (e.g. methyl cyanoacetate, ethylcyanoacetate) at reflux temperature of the solvent.

[0036] According to the step [e-1-a] or [e-1-b] of the presentinvention,2-cyano-2-[2-methyl-1-tosyl-5,6,7-trihydroindol-4-ylidene]acetic acidester can be produced in high yield using cyanoacetic acid ester, whichis very cheap reagent.

[0037] In the reaction scheme 3, the reaction of step [e-2] is a carbonelongation reaction, for example, [e-2-a] it is carried out using DeanStark equipment, in an organic solvent (e.g. toluene, xylene), in thepresence of ammonium acetate and an organic acid (e.g. acetic acid,propionic acid), using malononitrile at reflux temperature of thesolvent, or [e-2-b] it is carried out using Dean Stark equipment, in anorganic solvent (e.g. toluene, xylene, benzene), in the presence ofprimary amine (e.g. cyclohexylamine, n-octyl amine) and an organic acid(e.g. acetic acid, propionic acid), using malononitrile at refluxtemperature of the solvent.

[0038] According to the step [e-2-a] or [e-2-b] of the presentinvention,2-[2-methyl-1-tosyl-5,6,7-trihydroindol-4-ylidene]molononitrile can beproduced in high yield using malononitrile, which is very cheap reagent.

[0039] In the reaction scheme 2 and 3, the reaction of step [f] is ahalogenation reaction, for example, it is carried out in an organicsolvent (e.g. THF, dimethylformamide (DMF)), using base (e.g. sodiumhydride, lithium diisopropylamide, sodium t-butoxide, potassiumt-butoxide) at 20˜55° C., followed by using sulfonyl chloride(preferably cooled; e.g. benzene sulfonyl chloride, p-toluenesulfonylchloride, p-chlorobenzenesulfonyl chloride, p-nitrobenzenesulfonylchloride, trifluoromethanesulfonyl chloride) at −78˜30° C.

[0040] According to the step [f] of the present invention, the compoundsrepresented by the formula (V) and (VI), which is chlorinated at γposition, can be produced in high yield and γ-high selectivity againstthe chlorinated compounds at a position (the selectivity of γposition:αposition is 99:1 or more), under mild conditions suitable for industrialproduction. chlorination at γ-position chlorination at α-position

(V)

(VI)

[0041] In the reaction scheme 2 and 3, the reaction of step [g] is anaromatization reaction, for example, it is carried out in an organicsolvent (e.g. DMF, dimethylimidazolidinone, dimethylacetoamide,dimethylsulfoxide), using lithium halide (e.g. lithium bromide, lithiumchloride) or hydrate thereof at 80˜120° C. In the reaction scheme 4, thereaction of step [h] is a synthesis of enamine, for example, it iscarried out in an organic solvent (e.g. acetonitrile, THF,ethylenegylcol dimethyl ether, diglyme, isopropanol), using2-aminopropionaldehyde dimethyl acetal at reflux temperature of thesolvent.

[0042] The reaction of step [i] is a cyclization reaction, for example,it is carried out in an aqueous solution of an acid (preferably keepingat over 65° C.; e.g. p-toluenesulfonic acid, hydrochloric acid), addingthe solution of the compound prepared in step [h] in an organic solvent(e.g. acetonitrile, THF, ethyleneglycol dimethyl ether, diglyme,isopropanol) with keeping the temperature of the resulting mixture atover 65° C. (preferably keeping at over 70° C.).

[0043] According to the step [h] and [i] of the present invention,4-oxo-2-methyl-4,5,6,7-tetrahydroindole represented by formula (X) canbe produced in high yield.

[0044] The reaction of step [0] is (1) an introduction of anacetylmethyl group, and following (2) cyclization reaction. Anintroduction of an acetylmethyl group, for example, it is carried out ina water-miscible organic solvent (e.g. methanol, ethanol, isopropanol,acetonitrile), using a base (e.g. potassium hydroxide, sodium hydroxide,triton B), between room temperature and the reflux temperature of thesolvent for 5 to 10 hours. Then, cyclization reaction is carried out.The cyclization reaction is carried out in a water-miscible organicsolvent (e.g. methanol, ethanol, isopropanol, acetonitrile), using anammonium acetate, at room temperature to the reflux temperature of thesolvent for 1 to 5 hours.

[0045] According to the present invention, the compound represented bythe formula (X) can be produced in one-pot from the compound representedby the formula (XIV) without isolation process in each step.

[0046] Each reaction may be preferably carried out in an atmosphere ofinert gas (e.g. argon).

[0047] In each reaction step, the compounds using as starting materialare known per se, or may be prepared by conventional known method fromknown compound. Also, the reagents in the present invention are knownper se or may be prepared by known method.

[0048] In each reaction in the present specification, reaction productsmay be purified by conventional purification techniques, e.g. bydistillation under atmospheric or reduced pressure, by high performanceliquid chromatography, by thin layer chromatography or by columnchromatography using silica gel or magnesium silicate; or by washing orby recrystallization. Purification may be carried out after eachreaction or after a series of reactions.

[0049] The process for the preparation of indole-4-acetic acid, which issimilar to 2-methylindole-4-acetic acid represented by the formula (I)in the present invention, is published in (1) J. Org. Chem., 44(22),4003-4005 (1979) and (2) Hererocycles, 24(9), 2611-2618 (1986)hereinbefore described.

[0050] But, the starting materials and the reaction process in thepresent invention is completely different from that of the methoddescribed in (1). As for the method described in (2), expensive reagentis used in first step, and it is carried out under high temperaturecondition in second step. These methods are not suitable for industrialproduction. So, the methods described in these literatures do notsuggest the process for the preparation of the present invention, thatis suitable for industrial production using inexpensive reagents undermild conditions.

[0051] The process for the preparation of4-oxo-2-methyl-4,5,6,7-tetrahydroindole represented by the formula (X)in the present invention is published in (3) the specification of U.S.Pat. No. 4,868,315, (4) Justus Liebigs Ann. Chem., 655, 20-26 (1952) and(5) the specification of JP2-15058 hereinbefore described.

[0052] But as for the method described in (3), reverse-extraction, whichis complicated operation, is necessary. In the reaction scheme, thecompound has to be isolated. Moreover, in first and second steps, thereaction takes 2 or 3 days. These methods are not suitable forindustrial production. On the other hand, as for the method of thepresent invention, the reaction can be carried out between roomtemperature and the reflux temperature of the solvent. After thereaction was completed, the desired compound can be taken withoutcomplicated operation. And the starting material described in (4), isdifferent from that of the present invention. Ammonia is used at thereaction step, and this reaction is carried out under high temperature.So, the reaction must be carried out under heating in a closed equipmentsuch as autoclave, and it is irrelevance for industrial production. Onthe other hand, at the step [i] of the present invention, specialequipment is unnecessary, because of using ammonium acetate between roomtemperature and the reflux temperature of the solvent. As for the methoddescribed in (5), the starting material differs from them of the presentinvention. In the present invention, an isolation process of startingmaterial described in (5) is unnecessary.

[0053] As mentioned above, the step [j] of the present invention issuperior to any of the related arts.

[0054] The process for the preparation of the compound represented bythe formula (X), which is similar to4-oxo-2-methyl-4,5,6,7-tetrahydroindole in the present invention, ispublished in (6) J. Org. Chem., 43(18), 3541-3544 (1978) hereinbeforedescribed. But the yields of the compound 1 to compound 3, in which bothof R and R′ represent hydrogen atom, are low (33%). On the other hand,in the present invention, the desired compound can be obtained in highyield by changing an order of adding the compound, i.e., adding thecompound represented by the formula (XI) to p-toluenesulfonic acid andadjusting reaction temperature.

[0055] When the halogenation reaction described in (7) Hererocycles,23(1), 165-170 (1985) hereinbefore described applied to the compoundrepresented by the formula (VII) and (VIII), which is an intermediate ofthe compound in the present invention, the reaction does not proceed atall. The desired compound represented by the formula (V) or (VI) is notobtained. Moreover, it is reported that chlorinated by-product on2-position of indole-ring and chlorinated desired compound on 5-posotionare obtained in (7). The selectivity of chlorination on desired5-position is 86% (table 2). On the other hand, according to the processfor the preparation in this invention, the target compound chlorinatedat γ position can be produced in high yield and high γ-selectivity (theselectivity of γ position:α position is 99:1 or more). This metod ismore excellent than that of (7).

[0056] Thus, the synthetic route and reaction condition from thecompound represented by the formula (XIV) to the compound represented bythe formula (I) are novel and found out by these inventors for the firsttime. And 2-methylindole-4-acetic acid represented by the formula (I)can be produced in high yield using inexpensive reagents under mildconditions which are suitable for industrial production without specialequipment. The novel compound prepared by the method, which isrepresented by the formula (I), is used as an key intermediate formedicines.

BEST MODE FOR CARRYING OUT THE INVENTION

[0057] The following examples illustrate the present invention, but donot limit the present invention.

EXAMPLE 1 (1)

[0058] 4-Oxo-2-methyl-4,5,6,7-tetrahydroindole

[0059] Cyclohexan-1,3-dione (1.00 g) was dissolved in 1.7M solution ofpotassium hydroxide in methanol (85% potassium hydroxide (5.61 g) inmethanol (50 ml); 4.9 ml). To the solution was added chloroacetone (0.93ml) and the mixture was refluxed for 7 hours. The reaction mixture wascooled to room temperature. To the mixture was added ammonium acetate(756 mg) and methanol (4.5 ml), the mixture was refluxed for 2 hours.The reaction mixture was cooled to room temperature, adjusted the pH to6-7 with 4M aqueous solution of sodium hydroxide (1.7 ml), and thenconcentrated. To the residue was added dimethoxyethane (10 ml), and thenan insoluble was removed by filtration. The filtrate was concentated andthe residue was purified by column chromatography on silica gel (ethylacetate:hexane=1:1→ethyl acetate:hexane:methanol=5:5:1) to give thetitle compound (961 mg, 72.3%) having the following physical data.

[0060] TLC: Rf 0.85 (methanol:ethyl acetate=1:3);

[0061] NMR (200 MHz, CDCl₃): δ 8.64 (brs, 1H), 6.18-6.16 (m, 1H), 2.76(t, J=6.0 Hz, 2H), 2.48-2.41 (m, 2H), 2.23 (s, 3H), 2.18-2.09 (m, 2H);

[0062] MS (FAV, Pos.): 172, 150, 136;

[0063] IR (KBr): 3155, 1621, 1479, 1411, 1302, 1264, 1205, 1181, 1149,1128, 1047, 1014, 992, 899, 820, 740, 718, 627, 600, 575, 543, 418 cm⁻¹;

[0064] m.p.: 202.5-204.0° C.

EXAMPLE 1 (2)

[0065] 4-Oxo-2-methyl-4,5,6,7-tetrahydroindole

[0066] Cyclohexan-1,3-dione (1.00 g) was dissolved in 1.7M solution ofpotassium hydroxide in methanol (85% potassium hydroxide (5.61 g) inmethanol (50 ml); 4.9 ml). To the solution was added chloroacetone (0.93ml) and the mixture was refluxed for 7 hours. The reaction mixture wascooled to room temperature. To the mixture was added ammonium acetate(756 mg) and methanol (4.5 ml), the mixture was refluxed for 2 hours.The reaction mixture was cooled to room temperature, added water (6 ml),and then concentrated. The obtained crystal was washed with water (4 ml,twice) and dried to give the title compound (680 mg, 51.1%) having thefollowing physical data.

[0067] TLC: Rf 0.85 (methanol: ethyl acetate=1:3);

[0068] NMR (200 MHz, CDCl₃): δ 8.64 (brs, 1H), 6.18-6.16 (m, 1H), 2.76(t, J=6.0 Hz, 2H), 2.48-2.41 (m, 2H), 2.23 (s, 3H), 2.18-2.09 (m, 2H);

[0069] MS (FAV, Pos.): 172, 150, 136;

[0070] IR (KBr): 3155, 1621, 1479, 1411, 1302, 1264, 1205, 1181, 1149,1128, 1047, 1014, 992, 899, 820, 740, 718, 627, 600, 575, 543, 418 cm¹;

[0071] m.p.: 202.5-204.0° C.

EXAMPLE 2

[0072] 1-(3-Dimethoxypropyl-2-yl)amino-3-cyclohexenone

[0073] To a vessel were added 1,3-cyclohexanedione (5.00 g) andacetonitrile (24 ml) at 18° C. under an argon atmosphere. To the mixturewas added 2-aminopropionaldehyde dimethylacetal (5.58 g) during 2minutes at room temperature with stirring. After the addition wascompleted, the solution was stirred for 3 hours over 80° C. (internaltemperature). The reaction mixture was left overnight and the titlecompound was obtained having the following physical data.

[0074] TLC: Rf 0.50 (methanol:ethyl acetate=1:3);

[0075] NMR (200 MHz, CDCl₃): δ 5.14 (s, 1H), 4.65-4.62 (m, 1H), 4.23 (d,J=3.2 Hz, 1H), 3.67-3.58 (m, 1H), 3.45 (s, 3H), 3.43 (s, 3H), 2.35-2.28(m, 4H), 2.02-1.93 (m, 2H), 1.15 (d, J=6.8 Hz, 3H);

[0076] MS (FAV, Pos.): 236, 214, 182, 176, 154, 136;

[0077] IR (Liquid film): 3255, 3064, 2941, 2834, 1738, 1669, 1552, 1455,1432, 1369, 1319, 1257, 1191, 1134, 1067, 981, 968, 950, 937, 908, 859,809, 764, 672, 651, 610, 557, 535, 511, 468 cm⁻¹.

EXAMPLE 3 (1)

[0078] 4-Oxo-2-methyl-4,5,6,7-tetrahydroindole

[0079] To a 2M aqueous solution of p-toluenesulfonic acid (33.5 ml) atan internal temperature of ca. 80° C. was added dropwise the compoundprepared in example 2 at an internal temperature of ca. 70° C. whilekeeping the internal temperature of the mixture over 73° C. The mixturewas stirred for 2 hours at an internal temperature of ca. 80° C. Thereaction mixture was cooled to 25° C., adjusted the pH to 11 with 4Maqueous solution of sodium hydroxide, and then kept standing overnight.The solution was concentrated and then azeotroped with toluene. Theresidue was purified by column chromatography on silica gel(hexane:ethyl acetate=1:2) to give the title compound (4.78 g, 71.9%)having the following physical data.

[0080] TLC: Rf 0.85 (methanol:ethyl acetate=1:3);

[0081] NMR (200 MHz, CDCl₃): δ 8.64 (brs, 1H), 6.18-6.16 (m, 1H), 2.76(t, J=6.0 Hz, 2H), 2.48-2.41 (m, 2H), 2.23 (s, 3H), 2.18-2.09 (m, 2H);

[0082] MS (FAV, Pos.): 172, 150, 136;

[0083] IR (KBr): 3155, 1621, 1479, 1411, 1302, 1264, 1205, 1181, 1149,1128, 1047, 1014, 992, 899, 820, 740, 718, 627, 600, 575, 543, 418 cm⁻¹;

[0084] m.p. 202.5-204.0° C.

EXAMPLE 3 (2)

[0085] 4-Oxo-2-methyl-4,5,6,7-tetrahydroindole

[0086] To a 2M aqueous solution of p-toluenesulfonic acid (33.5 ml) atan internal temperature of ca. 80° C. was added dropwise the compoundprepared in example 2 at an internal temperature of ca. 70° C. whilekeeping the internal temperature of the mixture over 73° C. The mixturewas stirred for 2 hours at an internal temperature of ca. 80° C. Thereaction mixture was left for a while, adjusted the pH to 11 with 4Maqueous solution of sodium hydroxide. The 40% volumes of the reactionmixture was removed. The residue was stirred for 1 hour at roomtemperature, and then the appeared crystal was collected by filtration.The crystal was washed with water, and dried under reduced pressure for15 hours at 40° C. to give the title compound (3.73 g, 56%) having thefollowing physical data.

[0087] TLC: Rf 0.85 (methanol: ethyl acetate=1:3);

[0088] NMR (200 MHz, CDCl₃): δ 8.64 (brs, 1H), 6.18-6.16 (m, 1H), 2.76(t, J=6.0 Hz, 2H), 2.48-2.41 (m, 2H), 2.23 (s, 3H), 2.18-2.09 (m, 2H);

[0089] MS (FAV, Pos.): 172, 150, 136;

[0090] IR (KBr): 3155, 1621, 1479, 1411, 1302, 1264, 1205, 1181, 1149,1128, 1047, 1014, 992, 899, 820, 740, 718, 627, 600, 575, 543, 418 cm⁻¹;

[0091] m.p.: 202.5-204.0° C.

EXAMPLE 4

[0092] 2-Methyl-4-oxo-1-tosyl-4,5,6,7-tetrahydroindole

[0093] The compound prepared in example 3 (2) (111 g) was suspended inacetonitrile (1110 ml). To the suspension were added tetrabutylammoniumbromide (72 g) and 50% aqueous solution of sodium hydroxide (596 ml) atroom temperature. To the suspension was added dropwise a solution oftosylchloride (284 g) in THF (555 ml) at room temperature, and themixture was stirred for 1 hour. To the water (6700 ml) was added thereaction solution, and the mixture was stirred for 30 minutes at 15° C.The appeared crystal was collected by filtration, washed with water(1200 ml, twice) and dried under reduced pressure for 15 hours at 40° C.to give the title compound (219 g, 97.0%) having the following physicaldata.

[0094] TLC: Rf 0.75 (hexane:ethyl acetate=1:1);

[0095] NMR (200 MHz, CDCl₃): δ 7.65 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2Hz, 2H), 6.30 (s, 1H), 3.12 (t, J=6.0 Hz, 2H), 2.44-2.39 (m, 8H),2.18-2.05 (m, 2H);

[0096] MS (FAB, Pos.): 326, 304, 176;

[0097] IR (KBr): 3437, 2952, 1672, 1596, 1540, 1493, 1459, 1434, 1415,1366, 1304, 1258, 1238, 1215, 1193, 1166, 1131, 1094, 1052, 992, 902,835, 811, 782, 729, 701, 678, 653, 605, 585 cm¹.

EXAMPLE 5

[0098] Ethyl2-cyano-2-[2-methyl-1-tosyl-5,6,7-trihydroindol-4-ylidene]acetate

[0099] The compound prepared in example 4 (199 g) was dissolved intoluene (1990 ml) at 14° C. To the solution were added ammonium acetate(55.6 g), acetic acid (157.5 g) at 16° C., and ethyl cyanoacetate (111.8g). The mixture was refluxed for 19 hours while removing water usingDean Stark equipment. The reaction solution was concentrated and thenazeotroped with toluene. To the residue was added isopropanol (1990 ml)and water (995 ml) and the mixture was dissolved by heating. Aftercooling at ambient temperature, the mixture was cooled to an internaltemperature of 0° C. and stirred for 20 minutes. The appeared crystalwas collected by filtration. The crystal was washed withisopropaanol/water (900 ml/900 ml, twice) and dried for 13 hours at 60°C. under reduced pressure to give the title compound (192 g, 74.3%)having the following physical data.

[0100] TLC: Rf 0.63 (toluene:ethyl acetate=9:1);

[0101] NMR (75 MHz, CDCl₃): δ 7.64 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz,2H), 7.15-7.10 (m, 1H), 4.27 (q, J=7.2 Hz, 2H), 3.18-2.98 (m, 4H), 2.44(s, 3H), 2.43 (s, 3H), 2.00-1.80 (m, 2H), 1.35 (t, J=7.2 Hz, 3H);

[0102] MS (FAB, Pos.): 421, 399, 391, 353, 329, 307;

[0103] IR (KBr): 3754, 3678, 3449, 2934, 2216, 1714, 1655, 1596, 1536,1413, 1373, 1349, 1333, 1243, 1221, 1193, 1166, 1091, 1059, 949, 810,774, 704, 686, 652, 591, 544, 429 cm⁻¹;

[0104] m.p.: 124.1-125.9° C.

EXAMPLE 5 (1)

[0105] 2-[2-Methyl-1-tosyl-5,6,7-trihydroindol-4-ylidene]malononitrile

[0106] The compound having the following physical data was obtainedaccording to the same procedure as described example 5, usingmalononitrile instead of ethyl cyanoacetate.

[0107] TLC: Rf 0.82 (hexane:ethyl acetate=1:1);

[0108] NMR (200 MHz, CDCl₃): δ 7.66 (2H, d, J=8.5 Hz), 7.40 (2H, d,J=8.5 Hz), 6.96-6.90 (1H, m), 3.11 (3H, t, J=6.2 Hz), 2.80 (3H, t, J=6.2Hz), 2.46 (3H, s), 2.43 (3H, s), 2.10-1.90 (2H, m).

EXAMPLE 6

[0109] Ethyl2-cyano-2-[2-methyl-1-tosyl-5,6,7-trihydroindol-4-ylidine]acetate

[0110] The solution of the compound prepared in example 4 (80 g), ethylcyanoacetate (35.8 g), cyclohexylamine (5.23 g) and propionic acid (5.86g) in toluene (400 ml) was refluxed for 6 hours using Dean Starkequipment. The reaction solution was cooled and concentrated. To theresidue was added isopropanol (1360 ml) and the mixture was dissolved byheating. The solution was cooled and stirred for 14 hours at roomtemperature. To the solution was added water. The mixture was cooled at0° C. and then stirred for 1 hour. The appeared crystal was collected byfiltration, washed with isopropanol and dried to give the title compound(89.6 g, 85.3%) having the following physical data.

[0111] TLC: Rf 0.63 (toluene:ethyl acetate=9:1);

[0112] NMR (75 MHz, CDCl₃): δ 7.64 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz,2H), 7.15-7.10 (m, 1H), 4.27 (q, J=7.2 Hz, 2H), 3.18-2.98 (m, 4H), 2.44(s, 3H), 2.43 (s, 3H), 2.00-1.80 (m, 2H), 1.35 (t, J=7.2 Hz, 3H);

[0113] MS (FAB, Pos.): 421, 399, 391, 353, 329, 307;

[0114] IR (KBr): 3754, 3678, 3449, 2934, 2216, 1714, 1655, 1596, 1536,1413, 1373, 1349, 1333, 1243, 1221, 1193, 1166, 1091, 1059, 949, 810,774, 704, 686, 652, 591, 544, 429 cm⁻¹;

[0115] m.p.: 124.1-125.9° C.

EXAMPLE 7

[0116] Ethyl2-cyano-2-[5-chloro-2-methyl-1-tosyl-5,6,7-trihydroindol-4-ylidene]acetate

[0117] A sodium hydride (60˜72 wt %; 10.6 g) was suspended in THF (150ml) under an argon atmosphere and the mixture was stirred at an internaltemperature of 40˜50° C. To the suspension was added dropwise a solutionof the compound prepared in example 5 (100.4 g) in THF (400 ml) and themixture was stirred for 1 hour at an internal temperature of 45˜53° C.The reaction solution was cooled to room temperature.

[0118] A solution of benzenesulfonyl chloride (46.7 g) in THF (150 ml)was cooled at an internal temperature of −12˜10° C. To the solution wasadded dropwise the above mentioned reaction solution below an internaltemperature of 5° C. The mixture solution was stirred for 30 minutes at−10° C. To an aqueous solution of ammonium chloride (130 g/600 ml) wasadded the reaction solution, and then the mixture was extracted witht-butyl methyl ether (500 ml). The organic layer was concentrated togive the title compound (128.2 g) having the following physical data.The obtained compound was used for the next step without furtherpurification.

[0119] TLC: Rf 0.68 (toluene: ethyl acetate=9:1);

[0120] NMR (200 MHz, CDCl₃): δ 7.64 (d, J=8 Hz, 2H), 7.35 (d, J=8 Hz,2H), 7.11 (d, J=1 Hz, 1H), 6.42 (dd, J=3.6, 2.8 Hz, 1H), 4.33 (q, J=7Hz, 2H), 3.35-3.20 (m, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 2.50-2.30 (m,1H), 2.25-2.00 (m, 1H), 1.37 (t, J=7 Hz, 3H);

[0121] MS (EI, Pos.): 432, 397, 387, 369, 323, 277, 241;

[0122] IR (KBr): 3823, 2678, 3412, 2980, 2935, 2216, 1723, 1596, 1566,1492, 1475, 1428, 1373, 1347, 1247, 1191, 1159, 1089, 1057, 1028, 1005,942, 803, 781, 756, 703, 686, 674, 649, 598 cm⁻¹;

[0123] m.p.: 101.5-104.2° C.

EXAMPLE 7 (1)

[0124]2-[2-Methyl-1-tosyl-5-chloro-5,6,7-trihydroindol-4-ylidene]malononitrile

[0125] The compound having the following physical data was obtainedaccording to the same procedure as described example 7, using thecompound prepared in example 5 (1).

[0126] TLC: Rf 0.44 (hexane:ethyl acetate=2:1);

[0127] NMR (200 MHz, CDCl₃): δ 7.67 (2H, d, J=8.5 Hz), 7.38 (2H, d,J=8.5 Hz), 6.96-6.90 (1H, m), 5.24-5.08 (1H, m), 3.50-3.00 (2H, m), 2.46(3H, s), 2.42 (3H, s), 2.60-2.00 (2H, m).

EXAMPLE 8

[0128] Ethyl 2-cyano-2-[2-methyl-1-tosyl-indol-4-yl]acetate (8(a)) and4-cyanomethyl-2-methyl-1-tosylindole (8(b))

[0129] The compound prepared in example 7 (118.8 g) in DMF (470 mL) wasdissolved by heating. To the solution was added lithium bromidemonohydrate (24.5 g) and the mixture was stirred for 3 hours at aninternal temperature of 100˜105° C. After cooling to room temperature,the mixture was added to water (940 ml) and then extracted with ethylacetate (940 ml). The aqueous layer was extracted with ethyl acetate(940 ml) again. The combined organic layer was washed with an aqueoussolution of sodium bicarbonate (19.7 g/470 ml) and concentrated to givethe title compound (compound 8(a) and compound 8(b)) as mixture (105.7g) having the following physical data. The obtained mixture was used forthe next step without further purification.

[0130] Compound 8(a)

[0131] TLC: Rf0.49 (toluene:ethyl acetate=9:1);

[0132] NMR (200 MHz, CDCl₃): δ 8.30-8.10 (m, 1H), 7.68 (d, J=8.2 Hz,2H), 7.40-7.10 (m, 4H), 6.54 (s, 1H), 4.89 (s, 1H), 4.21 (dq, J=7, 1.4Hz, 2H), 2.64 (s, 3H), 2.37 (s, 3H), 1.22 (t, J=7 Hz, 3H);

[0133] MS (FAB, Pos.): 397, 391, 323, 307, 289;

[0134] IR (Liquid film): 3057, 2983, 2930, 1747, 1598, 1572, 1494, 1432,1390, 1370, 1307, 1293, 1256, 1221, 1189, 1178, 1159, 1122, 1099, 1068,1029, 1017, 925, 880, 856, 813, 777, 746, 705, 677 cm⁻¹.

[0135] Compound 8 (b)

[0136] TLC: Rf0.4 (toluene:ethyl acetate=9:1);

[0137] NMR (200 MHz, CDCl₃): δ 8.16 (d, J=7.6 Hz, 1H), 7.67 (d, J=8.4Hz, 2H), 7.32-7.15 (m, 4H), 6.44-6.36 (m, 1H), 3.83 (s, 2H), 2.64 (s,3H), 2.36 (s, 3H);

[0138] MS (FAB, Pos.): 347, 325;

[0139] IR (KBr): 3404, 3093, 2930, 2250, 1701, 1655, 1597, 1571, 1492,1431, 1407, 1370, 1297, 1258, 1221, 1176, 1098, 1062, 1041, 1011, 933,805, 777, 743, 704, 683, 645, 585, 561, 542 cm⁻¹.

EXAMPLE 9

[0140] 2-Methylindole-4-acetic Acid

[0141] To the mixture prepared in example 8 (97.7 g) was added ethanol(300 ml) and an aqueous solution of potassium hydroxide (121 g/490 ml)and the mixture was refluxed. After cooling to room temperature, themixture was concentrated. To the residue was added water (430 ml) andthe mixture was washed with t-butyl methyl ether (430 ml). The aqueouslayer was washed with t-butyl methyl ether again. An insoluble substancewas removed by filtration. The pH of filtrate was adjusted to 3 byconcentrated hydrochloric acid under ice cooling. The solution wasstirred for 30 minutes. The appeared crystal was collected byfiltration, and washed with water (220 ml, twice). The crystal wasdissolved in a mixture of isopropanol/water (122 ml/368 ml) underheating, and then the mixture was cooled to room temperature. Thesolution was permitted to stand for 1 hour at 4° C. The appeared crystalwas collected by filtration, washed with a mixture of isopropanol/water(1/3, 80 ml, twice) and dried for 19 hours at 40° C. to give the titlecompound (30.6 g, 74.8%) having the following physical data.

[0142] TLC: Rf 0.35 (Ethyl acetate);

[0143] NMR (200 MHz, DMSO-d₆): δ 11.0-10.8(br, 1H), 7.15(d, J=7 Hz, 1H),6.91 (t, J=7 Hz, 1H), 6.79 (d, J=7 Hz, 1H), 6.16-6.08 (m, 1H), 3.67 (s,2H), 3.62 (s, 3H);

[0144] MS (FAB, Pos.): 190, 170, 144;

[0145] IR (KBr): 3855, 3823, 3678, 3652, 3631, 3405, 2906, 1702, 1617,1557, 1509, 1439, 1405, 1348, 1295, 1278, 1253, 1214, 1178, 1056, 955,760, 708, 633, 513, 483, 420 cm⁻¹;

[0146] m.p.: 199.1-202.4° C.

EXAMPLE 10

[0147] 2-[2-Methyl-1-tosylindol-4-yl]malononitrile

[0148] The title compound having the following physical data wasobtained according to the same procedure as described example 8, usingthe compound prepared in example 7 (1).

[0149] TLC: Rf 0.33 (hexane:ethyl acetate=2:1);

[0150] NMR (200 MHz, CDCl₃): δ 8.40-8.20 (1H, m), 7.69 (2H, d, J=8.5Hz), 7.40-7.25 (2H, m), 7.23 (2H, d, J=8.5 Hz), 6.55-6.45 (1H, m), 5.18(1H, s), 2.66 (3H, s), 2.37 (3H, s).

EXAMPLE 11

[0151] 2-[2-Methylindol-4-yl]malononitrile

[0152] To the compound prepared in example 10 (232 mg) was addedpotassium hydroxide (740 mg), water (1.5 mL) and ethanol (0.8 ml) andthe mixture was refluxed for 23 hours. After cooling, ice-water and 6Mhydrochloric acid was added to the reaction mixture, and then themixture was extracted with t-butyl methyl ether. The organic layer wasdried over anhydrous magnesium sulfate and concentrated. The residue waspurified by column chromatography on silica gel to give the titlecompound (108 mg, 83.8%) having the following physical data

[0153] TLC: Rf 0.58 (toluene: ethyl acetate=2:1);

[0154] NMR (200 MHz, CDCl₃): δ 8.25 (brs, 1H), 7.41-7.24 (m, 4H), 6.36(s, 1H), 5.22 (s, 1H), 2.49 (s, 3H)

EXAMPLE 12

[0155] 2-Methylindole-4-acetic Acid

[0156] To the compound prepared in example 11 (48 mg) was added aceticacid (1 ml), water (1 ml) and concentrated sulfuric acid (1 ml), and themixture was stirred for 4 hours at 110° C. The reaction solution wascooled, poured into water and extracted with t-butyl methyl ether. Theorganic layer was dried over anhydrous magnesium sulfate andconcentrated. The residue was purified by column chromatography onsilica gel (hexane:ethyl acetate=1:1) to give the title compound (33 mg,70%) having the following physical data.

[0157] TLC: Rf 0.35 (Ethyl acetate);

[0158] NMR (200 MHz, DMSO-d₆): δ 11.0-10.8 (br, 1H), 7.15 (d, J=7 Hz,1H), 6.91 (t, J=7 Hz, 1H), 6.79 (d, J=7 Hz, 1H), 6.16-6.08 (m, 1H), 3.67(s, 2H), 3.62 (s, 3H);

[0159] MS (FAB, Pos.): 190, 170, 144;

[0160] IR (KBr): 3855, 3823, 3678, 3652, 3631, 3405, 2906, 1702, 1617,1557, 1509, 1439, 1405, 1348, 1295, 1278, 1253, 1214, 1178, 1056, 955,760, 708, 633, 513, 483, 420 cm⁻¹;

[0161] m.p.: 199.1-202.4° C.

1. 2-Methylindole-4-acetic acid represented by formula (I):


2. A process for producing the compound represented by formula (I):

comprising subjecting a compound represented by formula (II-a):

(wherein R¹ represents C1-4 alkyl; Ts represents tosyl group), acompound represented by formula (II-b):

(wherein Ts represents tosyl group) or a mixture thereof to hydrolysisreaction under alkali condition.
 3. A process for producing the compoundrepresented by formula (I):

comprising reacting a compound represented by formula (III):

with an acid.
 4. A process for producing the compound represented byformula (II-a):

(wherein symbols in the formula have the same meanings as describedabove), the compound represented by formula (I-b):

(wherein symbols in the formula have the same meanings as describedabove) or the mixture thereof according to claim 2, comprisingsubjecting a compound represented by formula (X):

to a tosylation reaction, reacting the resulting compound represented byformula (IX):

(wherein Ts represents tosyl group) with a cyanoacetate ester,subjecting a resulting compound represented by formula (VII):

(wherein R¹ represents C1-4 alkyl, and Ts represents tosyl group), to ahalogenation reaction, and reacting the resulting compound representedby formula (V):

(wherein symbols in the formula have the same meanings as describedabove) with a lithium halide or hydrate thereof.
 5. A process forproducing the compound represented by formula (III):

according to claim 3, comprising subjecting the compound represented byformula (X):

to a tosylation reaction, reacting the resulting compound represented byformula (IX):

(wherein Ts represents tosyl group) with malononitrile, subjecting theresulting compound represented by formula (VIII):

(wherein Ts represents tosyl group) to a halogenation reaction, reactingthe resulting compound represented by formula (VI):

(wherein symbols in the formula have the same meanings as describedabove) with a lithium halide or hydrate thereof, and subjecting theresulting compound represented by formula (IV):

(wherein symbols in the formula have the same meanings as describedabove) to a hydrolysis reaction under alkali condition.
 6. A process forproducing the compound represented by formula (X):

according to claim 4 or 5, comprising reacting a compound represented byformula (XIV):

with represented by a compound represented by formula (XI):

(wherein X represents halogen atom) between room temperature and areflux temperature of a solvent for 5-10 hours, followed by reactingwith ammonium acetate at room temperature to a reflux temperature of asolvent for 1-5 hours.
 7. A process for producing the compoundrepresented by formula (X):

according to claim 4 or 5, comprising reacting the compound representedby formula (XIV):

with a compound represented by formula (XIII):

and adding the resulting compound represented by formula (XII):

to an acid.